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Past Issues
Volume 15, number 4
April 2001
Contents
Kind of a Drag...
T-20's taking its sweet time getting here. Why?
Revolution!
Profound changes in attitudes to worldwide AIDS treatment
You Lost Me After the Title...
The fundamentals of reading scientific papers
What's HCV Got to Do, Got
to Do With It?
Does hepatitis C make HIV even worse
A TI Editorial
Women need to be better served by drug trials
What's Taking T-20 So
Long?
By Bob Huff
T-20 is the first member of a new class of anti-HIV drugs called
"fusion inhibitors" that are designed to block one stage of HIV's
entry into target cells. Because T-20 halts HIV at a unique point
in the virus's life cycle, it is expected to be active against viral
strains with diminished susceptibility to all currently available
antiretroviral drugs. This singular resistance profile is one reason
why the drug's sponsors, Trimeris, Inc. and Hoffman-LaRoche, have
guided the development of T-20 with an emphasis on use in so-called
"salvage" therapy.
When HIV infects a new target cell, it first binds to receptors
on the cell's surface where it undergoes a transformation of shape,
revealing a viral attachment protein called gp41. The gp41 protein
anchors a hook-like structure into the cell's membrane. Then the
gp41 pulls the virus package into contact with the cell's surface
where the lipid bilayers of the cell wall and the viral envelope
fuse and become one. After fusion occurs, the enzymes and RNA of
the virus are emptied into the cell where they begin to replicate
new virus.
T-20 is a small protein that matches a portion of the gp41 mechanism
thought to pull the virus into contact with a cell's surface. If
sufficient amounts of T-20 are present in the environment when gp41
is attaching itself to the target cell, the drug molecule will pair
with an exposed segment of gp41 and block the movement of the viral
envelope towards the cell surface. This is called fusion inhibition.
A sister compound, T-1249 works in a similar way but on a different
segment of gp41.
Since 1996, T-20 has moved through the first few stages of human
testing, demonstrating that it is safe enough to continue to use
and that it has anti-HIV activity at attainable doses. Now larger
Phase III trials have begun that are designed to show if the drug
is an effective treatment for reducing viral load when combined
with other, conventional, antiretroviral therapies.
However, parts of the research agenda for T-20, including a broad
expanded access safety study and a government-sponsored trial that
planned to include T-20 among several other experimental drugs for
patients with highly drug-resistant viruses, have been scaled back
or put on hold until a sufficient supply of T-20 becomes available
from the manufacturer. With early data indicating that T-20 can
safely contribute to viral suppression and a small amount of data
suggesting synergistic activity between T-20 and other experimental
entry inhibitors, the limited current capacity of the sponsor to
manufacture the drug deserves attention.
Making It
The production of T-20 on a commercial scale is a formidable task.
The sponsors are building a first-of-its-kind chemical manufacturing
plant in Boulder, Colorado, dedicated to synthesizing commercial
quantities of large peptide molecules such as T-20 and T-1249. The
current supply of T-20 for experimental purposes has been produced
in laboratories and more recently by contractors in small pilot
plants where the techniques of large-scale production are being
engineered.
Until viable production methods are established and the commercial
facility goes online, the pilot plants can only produce about 100
kilograms of T-20 per year. This is enough of the drug to supply
about 1200 patients annually. According to statements recently made
to investment analysts, the sponsors are projecting that the first
production batch will leave the Boulder plant early in 2002. Until
then, supplies of T-20 will be tight.
The long-awaited expanded access program, slated to begin this
summer, expects to only have enough T-20 to enroll 450 patients
worldwide, with 168 in the U.S. This is disappointing, given the
critical need many people have for a drug that attacks a new target
in the HIV life cycle. It is not expected that the supply situation
will improve much between now and when the new plant begins to produce.
The T-20 molecule itself bears little resemblance to those of current
AIDS drugs. The sixteen HIV drugs on the market in the U.S. are
all relatively small molecules that can be absorbed through the
intestines. They are also relatively cheap and easy to manufacture,
as we see from the recent availability of generic versions of antiretroviral
drugs made by firms in India and Brazil. In contrast, T-20 is a
huge molecule of a kind never before manufactured on a commercial
scale. It is also too large to be orally absorbed and must be injected
under the skin twice a day.
T-20 is a string of 36 amino acids called a peptide (a peptide
is really a small protein), and there are 14 different amino acids
that make up the chain of 36. Amino acids are commonly called "the
building blocks" of proteins. Proteins from food are digested into
amino acids, which are absorbed, distributed by the blood, then
used by the body to repair itself and to build the various proteins
and enzymes it needs to operate. Strings of amino acids like T-20
can't be taken orally because the proteolytic (protein chopping)
enzymes in the gut will break them down. The sequence of 36 amino
acids that makes up T-20 needs to stay intact for the drug to do
its work. Injecting T-20 under the skin bypasses the digestive enzymes
of the gut and puts the full-length molecule directly into the body.
In the laboratory, machines can make very small quantities of T-20
by adding one amino acid after another in sequence to create a chain.
When the peptide chain is complete, the molecules are separated
by weight, and partially or incorrectly formed peptides are filtered
out. But this process doesn't translate well into large-scale production.
To insure correct assembly of the chain and prevent unwanted reactions
that can't be easily controlled in the industrial setting, the amino
acid building blocks have to be processed in a way that "protects"
them until the chain is finished being built.
This is where it gets complicated. The manufacturer purchases the
protected amino acids from third-party specialty chemical makers.
The unprecedented quantities of "building blocks" required for the
production of T-20 initially exceeded the capacity and experience
of these suppliers. So, not only has the pharmaceutical company
had to dramatically scale-up its factory capacity, so have the vendors.
To insure a redundant backup supply, the manufacturer has decided
that at least two suppliers should be capable of providing each
crucial component. The system depends on over 125 outside vendors
to provide 45,000 kilograms of protected amino acids and other chemicals
just to produce 1000 kilograms of T-20. There are over 100 separate
steps to assembling a T-20 molecule. The novelty and complexity
of this process explains why supplies of T-20 will be limited until
the logistics of production are settled.
After the T-20 precursor is assembled, the protecting molecules
have to be removed and the remaining product must be purified. Then
the purified T-20 is freeze-dried (lyophilized), inspected, tested
for sterility, labeled and packaged. It takes about 10 weeks to
assemble a batch of T-20 and another 30 days to freeze-dry and package
the drug.
The next milestone for the manufacturer will be to produce a registration
batch of T-20 for submission to the FDA. The FDA will conduct stability
testing to determine the shelf life of the drug and to see if it
needs refrigeration to remain stable. When the registration batch
is submitted, the manufacturing process is officially frozen and
can't be changed without resubmitting product from the new process
for stability testing. Currently the sponsor expects to submit drug
samples for stability testing by the third quarter of 2001. After
the "lockdown" of the manufacturing process, larger, "validation"
batches will start to go into production. Monthly outputs of 100
to 200 kilograms are projected by early next year. People with AIDS
in need of new treatment options will expect the limited expanded
access program to "expand" considerably at that point.
Barring any breakdown in the complicated chain of chemical and
equipment suppliers, increasing quantities of T-20 should become
available each month up until the time of approval, when a capacity
of 400 to 600 kilograms per month is projected. Results from the
Phase III efficacy trials are expected to be reported at the 9th
Annual Retrovirus Conference in 2002. If this target is met, application
for approval could be submitted to the FDA during the following
six months. Though it's impossible to predict how the drug will
fare in its continuing clinical trials, two years from now to approval
may not be unthinkable. By mid-2003 the company anticipates being
able to treat 40,000 patients per year. The development of T-1249
is thought to be running about two years behind T-20.
Trimeris officials have pegged the expected profit margin of T-20
to be in line with that for protease inhibitors. The profit, of
course, will be added to the cost of making T-20. The price when
and if T-20 is approved? Don't ask.
| Relative size of HIV drug molecules |
Saquinavir
AZT
T-20
|
The Changing Outlook
for Worldwide HIV Treatment
By Gregg Gonsalves
The fight for affordable AIDS medications for the millions of poor
people living with HIV/AIDS across the globe is far from over, yet
one year ago, few would have predicted how far the struggle has
come since the International AIDS Conference in Durban last summer.
A revolution is happening in Africa. Largely due to the efforts
of the Treatment Action Campaign (TAC), a group of South African
people affected by HIV/AIDS, chances are improving that some of
the poorest people in the world may one day obtain the expensive
anti-AIDS medicines that have saved so many lives in the U.S. and
Europe. Founded in December of 1998, South Africa's TAC is arguing
for access to drugs that directly attack the virus that causes AIDS,
that treat the deadly opportunistic infections that kill people
with HIV/AIDS, and that block mother-to-child transmission of HIV.
Before the issue garnered headlines around the world, TAC was laying
the foundation for a radical revision of how the rich, industrialized
countries of North America and Europe should think about public
health in the developing nations of Africa, Asia and South America.
For most of the two decades of the AIDS epidemic, even after therapies
became available that clearly extended the health and lives of those
who took them, not many people gave serious thought to treating
the millions of people infected with HIV in developing countries.
Most of these millions are too poor and the drugs too expensive.
Instead, the world health community rallied around the hope for
an AIDS vaccine to prevent new infections, essentially writing off
the deaths of millions as a sad reality. But as the HIV-positive
South African High Court Judge Edwin Cameron has said:
"We don't accept 'sad realities' in South Africa. If we accepted
what others told us were sad realities, we would still have had
a racist oligarchy oppressing our people. We would have had indescribable
chaos and bloodshed. We have shown through our history that we will
confront those 'sad realities,' and we will change them."
And change them, they have. Led by TAC (and a few other organizations,
including the Nobel Prize-winning Doctors without Borders), there
is now a global call to drastically reduce the prices of these expensive
drugs and to allow the manufacture and importation of cheaper generic
copies of patented medications. Many argue that the violation of
pharmaceutical patent protections by poorer nations is permitted
by international trade agreements allowing compulsory licensing
and parallel importing in cases of national emergency, such as the
AIDS epidemic.
The pharmaceutical companies have fought back. The South African
Pharmaceutical Manufacturers Association and forty multinational
drug companies (including GlaxoSmithKline, Merck, Bristol-Myers
Squibb, Boehringer-Ingelheim and Roche) are challenging that country's
Medicines and Related Substances Control Amendment Act. The Medicines
Act, passed by the South African Parliament and signed into law
by Nelson Mandela in 1997, contains several provisions intended
to make essential medicines more accessible and affordable to its
citizens. GlaxoSmithKline (GSK) has also warned generic manufacturers
against supplying Ghana and Uganda with cheaper versions of its
drugs lamivudine (3TC) and zidovudine (AZT). In a November, 2000,
letter to Cipla Limited, the Indian generic drug maker, GSK barked:
"Importation, sale or offering for sale of products containing
lamivudine and zidovudine in Uganda by Cipla or any of its affiliates
represents an infringement of our Company's exclusive patent rights.
I look forward to your assurance that you will cease all infringing
activity in Uganda and respect the above mentioned patent rights."
Activists here in the U.S., led by the HealthGAP Coalition, the
AIDS Coalition to Unleash Power/Philadelphia and the Consumer Project
on Technology, have been successful in getting the federal government
to moderate its unqualified support for industry on this issue.
In December, 1999, President Clinton issued an Executive Order that
allows countries in sub-Saharan Africa to pursue the manufacture,
importation, and use of generic anti-AIDS drugs without the threat
of U.S. government intervention to block their actions. To the surprise
of many, the new Bush administration has announced that it will
maintain the Clinton order.
However, the U.S. has asked the World Trade Organization to initiate
a dispute resolution procedure against Brazil over one of its patent
law provisions that allows compulsory licensing for products that
are not produced locally. While the U.S. Trade Representative's
office has assured activists that there are other provisions in
Brazilian law that allow compulsory licensing of pharmaceuticals
— specifically in the case of national emergency — many
are worried that the U.S. actions will have a chilling effect on
Brazil's successful AIDS program. The Brazilian approach has used
locally produced generic versions of antiretroviral medications
to treat approximately 100,000 people living with HIV/AIDS, sparing
them from unnecessary suffering and death. In addition, the U.S.
government is now pushing for stringent intellectual property provisions
in the Free Trade Agreement of the Americas, which are more restrictive
to compulsory licensing than current international agreements. These
provisions, if enacted, could hinder the implementation of effective
AIDS treatment programs like Brazil's in over thirty nations in
North, Central and South America and the Caribbean.
Lately, the pharmaceutical industry has been feeling the heat.
In February 2001, Cipla offered to supply HIV triple-combination
therapy (i.e., stavudine, lamivudine and nevirapine) for $350 per
patient per year to Doctors without Borders, and to sell the therapy
for $600 per patient per year to poor governments. After the Cipla
offer, and amid growing concern in the industry over a tarnished
public image, several big AIDS drug makers have significantly dropped
the prices of their patented antiretroviral medications in the developing
world. While these price cuts are welcome (and belie the notion
that industry cannot afford to sell these drugs in the developing
world at reduced prices), many of the offers come with restrictions
in the fine print that limit the reductions to only certain countries
or regions. This patchwork-pricing plan leaves the drugs still out
of reach for many nations and still more expensive than generic
versions offered by Cipla and others. For instance, Merck said they
would not offer Brazil the yearly per person price of $600 for Crixivan
and $500 for Stocrin (efavirenz) that South Africa had been offered.
Merck claimed that Brazil is not as needy as other countries, yet
some activists wonder if Brazil has been targeted for its willingness
to make its own generic antiretroviral drugs. Indeed, Brazil has
threatened to start producing a generic version of Stocrin this
summer if prices don't come down. In retaliation, Merck threatened
to take legal action against a Brazilian laboratory when they imported
a generic form of Stocrin from India as the first step towards copying
the drug. As we went to press, Merck had struck a deal with the
Brazilian government to lower the prices of its two antiviral drugs,
proving once again that generic competition (or the prospect thereof)
can drive prices down. Whether the deal holds needs to be watched
carefully.
Last summer, many of us who went to the International AIDS Conference
in Durban listened glumly as South African President Thabo Mbeki
questioned whether HIV was the cause of AIDS. In a protest march
to the conference center through the streets of Durban, the women
and men of TAC were asking a different, altogether more important
question: Why should some people have the privilege of purchasing
their life and health when 34 million people in the resource-poor
world are falling ill, feeling sick to death, and are dying? Justice
Cameron posed this very question in a speech that same week. For
Justice Cameron this "seems a moral inequity of such fundamental
proportions that no one can look at it and fail to be spurred to
thought and action about it." The world is beginning to rise to
his challenge.
While prices from industry are not yet at the level that make them
affordable to many countries, many people are now pondering how
to deploy antiretroviral therapy in these regions. How do you procure
these drugs in bulk? How do you distribute them? How do you build
up the health care infrastructure in those places that need additional
resources in order to deliver these drugs to patients? How do you
train doctors and other healthcare providers in the painstaking
details of treating HIV/AIDS? How do you medically manage antiretroviral
therapy in resource-poor settings? Few dared to move beyond a theoretical
consideration of these questions a year ago.
The pharmaceutical industry has made some public concessions but
as yet they've shipped no drugs. Lately, they've been flexing their
formidable public relations muscle to try to lower expectations
— recently a flurry of articles and op-ed pieces have appeared
questioning the feasibility of ever solving the infrastructure problems
of Africa. We've made considerable progress during the past year
but the challenges posed by Justice Cameron will not be met until
the tide of suffering and death is stemmed.
How to Read a Scientific
Paper
By Carlton Hogan, University of Minnesota, Coalition for Salvage
Therapy
(First of a three-part series)
Part One:
So Many Papers, So Little Time:
What Can I Trust?
When it comes to coverage of health issues on TV and in the papers,
it seems like the media has a new, and often contradictory, story
every week. First eggs are cholesterol-laden orbs of death, then
they're a great source of protein. One day, estrogen replacement
can protect against heart disease in older women, the next day it
can't. Last year, a high-fiber diet was said to be your best protection
against colon cancer, now they say it's irrelevant (although anything
that gets you to eat all your veggies can't be too bad).
In a complex and fast-paced field like AIDS research, the confusion
can be even worse. Every single month, over a hundred scientific
articles and conference presentations come out, each intended to
expand our knowledge about HIV. And that's not even counting all
the reports (like basic immunology studies) that are key to understanding
HIV/AIDS but are not technically "AIDS research." While many of
these scientific reports help piece together the jigsaw puzzle of
HIV, filling in a picture of the virus and its nefarious activities,
the absolute truth may be as difficult to grasp here as it is in
the mainstream media.
Two years ago d4T (Zerit) was widely thought to be the least toxic
of all the NRTIs (nucleoside reverse transcriptase inhibitors: drugs
in the same class as AZT, ddI and abacavir). More recently, findings
suggest that d4T may be one of the prime suspects for causing damage
to mitochondria (energy "factories" within our cells). Similarly,
not long ago, missing a single dose of one's antiretroviral medication
was thought to be risking catastrophe. In 2000, our spring fashion
line featured the concept of strategic treatment interruption (STI)
as the next great hope.
The Internet, while being an indispensable research tool, literally
bringing the libraries of the world to our fingertips, has also
increased the deluge of information. Now hundreds of articles —
some in agreement, some contradictory — vie for our attention,
along with the commentary of experts pointing out confirmation of
their pet theories — and refutation of their rivals' —
in the newest research.
How can we make sense of this? Obviously not all research is equally
good or useful. How can a healthcare consumer critically evaluate
this torrent of information? When two reputable sources disagree,
how do we make sense of it? Do we have to believe one over the other
or do we try to find some useful synthesis?
The highly technical language of most papers doesn't help matters.
While much of the jargon serves as a kind of "shorthand" among scientists
to refer to common methods or basic findings, it can make scientific
papers difficult or impossible to understand for those who aren't
involved in the field.
The good news is that there are some common rules and conventions
for writing science reports that make reading, understanding and
interpreting the results much easier. Certain standards and terminology
are universal, whether one is discussing immunology or botany. I
hope to provide you with an understanding of these conventions and
how they are used — and misused. While it's probably a good
policy to mistrust anyone who claims to have the one and only answer
to a controversy, it's a lot easier to evaluate someone's claims
(or your own discoveries) when you have a good understanding of
the scientific conventions.
Anatomy Lesson (The Components of a Research Paper)
Before we dig into the specifics of analyzing a research paper,
let's take a look at how scientific reports are organized and how
the information is presented. Usually, the basic structure of a
scientific paper is the same, whether it's about AIDS or nuclear
physics. Roughly speaking, you can always expect to find these sections
in a paper:
- the abstract
- the background and rationale
- a description of the methods used
- the actual results, and finally
- the discussion — the author's interpretation of the results.
Hopefully the discussion makes sense of the results within the
context of the issues that were raised in the background and rationale.
Let's take a closer look at each of these sections.
1. The abstract
The abstract isn't technically a part of a paper, rather it's the
"Reader's Digest" version: a short synopsis that summarizes the
key points. These key points should give you a brief recap of each
part of the paper listed above. Generally when one consults Medline,
AEGIS, or other on-line information sources, an abstract is all
that's available. The abstract is an invaluable tool that can help
you decide which papers are worth getting and reading in their entirety.
As a tool for fully understanding the research, abstracts have substantial
limitations. Specific details beyond those necessary to convey the
main finding are scarce. Often the description of methods is cursory
or missing, making it hard to assess the scientific rigor of the
study. Only the primary results are summarized, omitting potentially
valuable supporting data. Still, abstracts play an indispensable
role by allowing you to quickly extract the gist of a paper.
2. Background and rationale
The background and rationale section tells you the reasons why
the paper was written. It describes previous related research, identifies
the questions that are still unanswered and proposes exactly what
the paper will address. For the purposes of this article I will
refer to an imaginary antiretroviral drug I call "X-100" to provide
examples. (X-100 does not exist, and all the data relating to X-100
is for illustration purposes only.)
In a paper describing the usefulness of X-100 for patients who
have previously failed a protease inhibitor (PI), the background
and rationale should explain why the X-100 experiments were done
in the first place. It might discuss the rate of virologic failure
in patients treated with PIs, the clinical implications of virologic
failure, and why new therapies like X-100 are needed. Next, it might
give us some background on X-100 itself: its basic chemistry and
research results, including in vitro (in the laboratory) activity,
animal studies, and any human research to date. The background and
rationale is exactly what it sounds like. It provides you with the
basic context of the research, and offers the rationale (reason)
why this particular study is needed. It should also describe the
primary hypothesis (the key question that drives the research) as
well as any secondary objectives.
3. Methods
The methods section is one of the most important, and also most
neglected, parts of a scientific paper. Here the investigators describe
exactly how they did the research: how they set it up, what measurements
were taken, what mathematical methods were used to analyze the data,
etc. The methods section is where eligibility criteria (who was,
and was not, allowed in a clinical trial) and endpoints (the exact
definition of what is to be measured, and why) are defined. It is
also in the methods section that the primary hypothesis and secondary
objectives (introduced in the rationale) are specified in full detail.
In the case of our fictional "X-100" trial, the hypothesis might
go something like this: "In adults with CD4 counts between 50 and
300, who have HIV RNA (viral load) of over ten thousand while on
a protease inhibitor containing regimen, X-100 provides a greater
and more prolonged decrease in HIV RNA compared to an optimized
regimen using approved agents, guided by genotypic resistance testing."
The study then attempts to prove (or disprove) this hypothesis.
Secondary objectives might compare X-100 with standard treatments
on the bases of toxicity, quality of life, or other important considerations.
In this age of high technology, with sophisticated tests like HIV
RNA, sometimes the focus drifts from the specific and detailed construction
of the hypothesis. It's tempting to add all kinds of extra measurements
to a trial without first being clear about exactly what questions
they will address. More than one scientist has observed that properly
framing and describing the research question is half the job. By
starting with a clearly thought out and well-described research
question, much of the subsequent planning is just filling in blanks
for the specifics that are dictated by the nature of the question
itself. [One amusing sociological side note on the methods section:
At scientific conferences you can always spot someone who works
in the same field as an author — they jump straight to the
methods section, just as others tend to skip past it. But after
all, if they're in the same discipline, they hardly need convincing
of the background and rationale!]
4. Results
The heart of a paper, the results section presents the actual findings
of the study. You also will read a description of what the conditions
were at the start of the trial. In our fictional X-100 trial, we
might see a summary of the patients' baseline (at the beginning)
CD4s, their viral loads, their history of AIDS-related conditions,
and, since this is a salvage trial, probably a summary of their
previous treatment histories. In terms of the actual results themselves,
we might expect to see the average viral loads of the group who
got X-100 compared to those who didn't. We also might see information
about the duration of response, relative rates of clinical disease,
toxicities, and other objectives of the trial. We can certainly
expect to see all the data relating to the objectives described
in the methods section. Editorializing about the meaning and implications
of the results is supposed to be restricted to the discussion section.
Rarely are things divided this neatly, though, and the results section
can contain a fair amount of analysis and sometimes, spin.
5. Discussion
This is where the authors try to wrap up the whole package. The
findings are discussed in the context laid out in the background
and rationale, and the significance of the results is established.
In general, this is the most editorial section of the paper, where
authors not only discuss the raw data, but attempt to generalize
(extend) these findings to groups of people who were not in the
trial. By nature, some speculation is not only tolerated but expected,
even if it's as bland as "X-100 holds great promise for the treatment
of HIV-infected individuals failing existing therapies."
Now that we have discussed how a paper is constructed, we can get
to the interesting stuff — the actual contents of the paper.
Of the thousands of papers published every year, some are far more
reliable and relevant than others. There are certain specific characteristics
you can look for when deciding which papers to trust and use for
making important decisions.
Who is Telling You This?
It may seem very obvious, but one of the most important criteria
for evaluating any piece of information is to consider its source.
Many people feel more comfortable with research coming from a university
or the National Institutes of Health than if it comes from a drug
company. It's only recently that most research designed to lead
to U.S. Food and Drug Administration approval of a company's new
drug application (NDA) has primarily come from trials conducted
by drug companies or by hand-picked teams of investigators. These
studies are often the first and only source of information available
about a new drug. Obviously it would be na•ve and unproductive to
ignore this research just because of the source, but knowing the
source can certainly help you to critically evaluate the research,
and may affect how much you are willing to take on faith.
Sad as it is, it's not just drug companies that have a personal
stake in "favorable" research results. The careers of modern-day
academics flourish or die based on the papers they publish. And
rarely does anyone publish papers with negative results (those where
the experiment failed). So there's considerable psychic pressure
on everybody involved with trials to produce positive research results.
Furthermore, many people feel that data is inherently less trustworthy
when it's been summarized and presented by someone with a financial
stake in the outcome. Fortunately, more and more journals are adopting
policies that obligate investigators with a financial stake in the
research results to disclose their interests.
One relatively little-known fact is the significance of the last
author listed. Obviously, everybody looks at the name of the lead
author. The research is likely to be their personal project and
they probably have more tied up in terms of time, thought, and effort
than anyone else (although let's not forget the grad student who
is probably listed fifth or sixth). But the last author in the list
is usually the senior scientist in whose lab the work was done.
So intramural (on-campus) research at the National Institutes of
Allergy and Infectious Disease (NIAID) always lists Anthony Fauci,
the director of NIAID and its several labs, as the last author,
even when his only participation was advisory.
Looking Forward, Looking Back
(Prospective vs. Retrospective Designs)
One of the things that can most affect the usefulness and generalizability
of a study is whether it was prospective or retrospective. A prospective
study is an experiment that is designed to answer a specific question
(prospective — meaning literally "looking forward"), with every
aspect of the design meant to facilitate getting that particular
answer. Alternatively, a retrospective study starts with a bunch
of information that was collected for some other purpose (maybe
not even with research in mind. Clinic charts are a good example).
The investigator then tries to answer a new question by piggybacking
onto the existing set of data.
Retrospective designs can never produce the kind of convincing
results that prospective studies can, for reasons I will shortly
discuss. However, prospective designs are not always practical or
possible. For example, if we wanted to know if the introduction
of HAART had a major impact on AIDS-related dementia, we would have
to look at people from the pre-HAART era to make that comparison.
This is a question we simply cannot answer prospectively today.
It would be criminal to deprive PWAs of optimal treatment simply
to do that study.
Sometimes there may be only a narrow window of time during which
one can answer a question prospectively. In the example above, dementia-related
questions could have been included in the initial trials of HAART
when the new combinations were being compared to only one or two
drugs. Today, however, we know that HAART is effective and that
no one should be denied it. But in the case of our mythical X-100,
since we don't really know what effect it has yet, we have a unique
opportunity to collect some neurocognitive data that lets us compare
X-100 to standard HAART for prevention of dementia.
One of the biggest problems with retrospective data is that we
have no idea who was excluded from the data set, and why. For example,
if we used chart review to try to get an idea of who had dementia
in the early nineties, we might stumble into some unexpected pitfalls.
It's possible that one particular clinic had a very good relationship
with the neurology clinic, so that all potential dementia cases
were taken to neurology for evaluation and diagnosis. This clinic
might report a high rate of dementia. Another clinic that serves
many people with multiple addictions might not carefully distinguish
between early dementia and other cognitive problems. They'd report
a low rate of incidence. One of the biggest problems with missing
data is that, by definition, we don't know how much data are missing
or why they are missing. One of the advantages of a prospective
design is that we can make sure that all participants have, say,
their neurocognitive functions measured in the same way at baseline,
so that we do not have to compare apples and oranges.
Next Month
In our next installment, we'll look at inclusion and exclusion
criteria, endpoints, and then we'll flip a few coins to understand
the role that chance plays in all of this.
If you live in New York and would like to read some of the scientific
information about HIV/AIDS, visit GMHC's Treatment Education Library.
The address is 119 West 24 Street on the 7th floor.
The Treatment Library offers a wide range of information about
HIV/AIDSÑfrom easy-to-read pamphlets to the latest scientific journals.
The friendly staff can also help you search for information and
abstracts on the Internet. Basic classes on using the Internet are
offered for people living with HIV/AIDS. Call 212/367-1458 for more
information or to make an appointment to use the library.
Does HCV Negatively Impact
on HIV Disease Progression and Survival?
By Michael Marco, Treatment Action Group (TAG)
It is often stated that the rate of progression to cirrhosis for
individuals infected with hepatitis C virus (HCV) may be accelerated
for persons also infected with HIV who have CD4+ counts less than
200 cells/mm3. A recent paper in the British medical
journal, The Lancet, and a number of studies presented at
the 8th Annual Retrovirus Conference have reported on attempts to
answer a parallel question about HIV-HCV coinfection: Does infection
with HCV have a negative impact on HIV disease progression and survival?
The best data are from the well-established European HIV cohorts
and a group at Johns Hopkins University in Baltimore, Maryland.
But results remain contradictory and the question is begging for
more research.
Studies Concluding "Yes."
A large, prospective study from Greub and colleagues1
of the Swiss HIV Cohort was recently published in The Lancet. Patients
initiating HAART between June 1996 and May 1999 were followed for
survival, clinical progression, HIV RNA suppression, CD4 cell recovery,
and number of HAART changes according to HCV status. Of the 3,111
HIV patients who were followed for a median of 28 months, 1,157
(37.2%) were coinfected with HCV, 1,015 (87.7%) of these with a
history of IDU. There were significant differences in baseline HIV
characteristics between the HCV-infected and HCV-uninfected patients:
27.7% vs. 23.5% had AIDS; 58.9% vs. 52.3% were antiretroviral treatment
(ART) naive; and median CD4 cell counts were 172 vs. 222 cells/mm3.
After the initiation of HAART, there was no association between
HCV infection and the probability of reaching an HIV RNA of <400
copies/mL. Approximately 87% of all patients suppressed their HIV
RNA to <400 copies/mL. There were, however, differences between
the two groups with regard to CD4 cell recovery. After one year
on HAART, the probability of failing to increase one's CD4 count
by 50 cells/mm3 was 25.1% for HCV-infected patients compared
to 16% for the HCV-uninfected patients.
At the end of follow-up, 7.5% of the HCV-infected patients in the
Lancet study developed an OI compared to 4.7% of the HIV-only patients.
Death from all causes was also more common in the HCV-infected patients:
8.8% vs. 4%. Interestingly, there were significant differences in
the probability of clinical progression to AIDS and death when data
were stratified by active injection drug use (IDU) and HCV infection.
The estimated probability of clinical progression at 2 years was:
6.6% for HIV-only/no active IDU; 9.7% for HCV-positive/no active
IDU; and 15% for HCV-positive/active IDU.
This study is one of the first (and largest) to detect an increase
in OI and death due to coinfection with HCV. One explanation for
this could be the impaired CD4 cell recovery in HCV-infected patients
on HAART. Other factors could involve the quality of healthcare
that current and former IDUs are likely to receive. These results
need to be confirmed in another study of equal size in a different
country. The fact that over 85% of these 3,000 Swiss patients had
HIV RNA under 400 copies/mL makes this author suspect that Switzerland
does not represent the "real world" when it comes to HIV and its
medical management.
At the 8th Annual Retrovirus Conference, Klein and colleagues2
from Montreal's McGill University presented results from a chart
review of 182 HIV-positive patients that also suggested HCV coinfection
was associated with increased hospitalizations and faster progression
to death. Seventy-eight HIV/HCV coinfected patients were compared
with 104 patients infected with HIV only. All were seen at the McGill
clinic between January 1996 and June 1999. While both groups had
similar baseline demographic characteristics, only 23% of the coinfected
patients were on HAART compared to 35% of the HIV-only patients.
Coinfected patients tended to have poorer outcomes (expressed here
as the number of events per 100 patient years): the rate of opportunistic
infections (OI) was 9.77 vs. 7.91; deaths, 6.67 vs. 2.27; and hospitalizations,
15.03 vs. 6.79 in coinfected and HIV-only patients, respectively.
The authors speculated that the differences in HIV clinical progression
"may be explained in part by the lower use of HAART" and "by increased
co-morbid factors associated with injection drug use" among coinfected
patients. The data here are interesting, but it is difficult to
garner definitive conclusions from such a small, retrospective single-institution
case study.
Impairment of CD4 cell recovery in HIV/HCV coinfected patients
on HAART was also noted in a Spanish study conducted by Martin and
colleagues3 from Vincent Soriano's group. A cross-section
"snapshot" of 902 HIV-positive patients (72% coinfected with HCV)
who attended an HIV clinic between January 1998 and April 2000 observed
significant differences in CD4 count and viral load between HCV-infected
and HIV-only patients, respectively: mean CD4 count was 518 vs.
620 cells/mm3 and HIV RNA was approximately 11,000 vs.
6,000 copies/mL. Similar proportions of patients in each category
were receiving ART (~92%) and there was no reported difference in
drug adherence (83% taking >90% of pills).
In a longitudinal analysis over a two year interval, there were
striking immunologic and virologic differences between the two groups.
HIV RNA on average declined by only 606 copies/mL in the HCV-infected
group compared to 5,788 copies/mL in the HIV-only group. Likewise,
CD4 counts on average increased by 53 cells/mm3 (11%)
compared to 111 cells/mm3 (22%) in the HCV-infected and
HIV-only groups, respectively.
The authors raise an interesting point for HIV-treating physicians
to ponder: would treating a coinfected patient's HCV (regardless
of liver fibrosis state) indirectly help combat the underlying HIV
disease?
Does HCV Negatively Impact on HIV Disease Progression and Survival?
Studies Concluding "No."
Data from the Johns Hopkins 1,742 patient HIV cohort suggest that
HCV coinfection does not affect HIV disease progression or survival.
Sulkowski and colleagues4 prospectively followed this
cohort, 45% of whom were HCV-infected, from January 1996 to June
2000 and observed outcomes of CD4 cell decline to under 200 cells/mm3,
development of OI, and death. HCV-infected patients were older,
more likely to be black (85% HCV+ vs. 65% HCV-negative) and had
past or present IDU (85% HCV-positive vs. 14% HCV-negative), yet
no differences were observed in baseline CD4 and HIV RNA.
When HAART use and lack of HIV RNA suppression to <400 copies/mL
were controlled for in a multivariate analysis, HCV infection was
not significantly associated with CD4 decline or survival (relative
hazard = 1.18). Use of HAART and lack of HIV RNA suppression remained
significant in the multivariate analysis. Of interest, impairment
of CD4 cell recovery on HAART was also noticed in the coinfected
patients at Hopkins. With three studies2,3,4 reporting
this fact, TAG believes that intensified research on the immunology
of HCV coinfection is warranted.
Two other studies presented at the 8th CROI — one French,
one Spanish — also failed to document an increased rate of
HIV clinical progression or mortality in coinfected patients. Rancinan
and colleagues5 performed a retrospective analysis of
995 HIV-positive patients from the French Aquitaine Cohort (58%
of whom were coinfected with HCV). No significant increase in risk
of AIDS or death was noted in the HCV-infected patients compared
to the HIV-only patients. In Macias and colleagues'6
504 patient Seville HIV cohort, deaths due to liver failure have
increased since 1997, yet no significant difference in survival
was observed between HCV-infected and HIV-only patients.
The debate over whether HCV alters HIV clinical progression adds
to the growing list of questions for clinical and basic research
into HIV/HCV coinfection. In this fledgling field we desperately
need large, prospective, collaborative, natural history studies
(as well as treatment trials) in the U.S. and abroad and the financial
resources to implement and carry them out with proper follow-up.
Footnotes:
1. Greub G, Leergerber B, Battegay M, et al. Clinical progression,
survival, and immune recovery during antiretroviral therapy in patients
with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort
Study. Lancet 356: 1800Ð5, 2000.
2. Klein MB, Lalonde RG, Suissa S. Hepatitis C (HCV) co-infection
is associated with increased morbidity and mortality among HIV-infected
patients [abstract 596]. 8th CROI, Chicago, 2001.
3. Martin J, Lopez M, Arranz R, et al. Impact of hepatitis C in
HIV-infected individuals in an urban center in Madrid, Spain [abstract
572]. 8th CROI, Chicago, 2001.
4. Sulkowski M, Moore R, Mehta S, Thomas D. Effect of HCV coinfection
on HIV disease progression and survival in HIV-infected adults [abstract
34]. 8th CROI, Chicago, 2001.
5. Rancinan C, Neau D, Saves M, et al. Does hepatitis C virus (HCV)
coinfection modify survival in HIV patients on combinations of antiretrovirals?
[abstract 570]. 8th CROI, Chicago, 2001.
6. Macias J, Pineda JA, Melguizo I, et al. Influence of hepatitis
C virus (HCV) infection on mortality of patients with HIV disease
under highly active antiretroviral therapy (HAART) [abstract 571].
8th CROI, Chicago, 2001.
A Treatment
Issues Editorial
We Need to Know More about How HIV Drugs
Work in Women
Community advocates routinely remind clinical trial sponsors how
important it is to insure that drugs are studied in women. Trial
sponsors routinely say they agree and want to do better as they
recite the percentages of women in their studies. The advocates
then point out that it is not sufficient to merely increase the
representation of women in a study to reflect their proportion of
the epidemic. To obtain statistically significant results, there
should be enough women enrolled to allow an independent analysis.
That's when the meeting peters out.
The representation of women in clinical trials should be increased.
Sponsors can start by conducting more trials at sites that treat
large numbers of women. If studies continue to run primarily at
centers that serve mostly men, then little will change. This may
require investment in training and capacity to develop new research
sites, but it's a small price to pay if we can better generalize
the results. Our commitment to community-based research also needs
to be reaffirmed — even as our expectations for its performance
are increased.
But simply (or not so simply) increasing the proportion of women
enrolled in trials does not address the call for statistically significant
results. The sample sizes of drug efficacy trials are chosen to
yield convincing results with the contribution of data from every
participant. Unless the study drug is a blockbuster, conclusions
that rely on only a subset of the data can never be as sure as those
from a full analysis. The only way to have equal confidence in the
results for both men and women is to enroll equal numbers of each.
That's not likely to happen. Clinical trials for efficacy are expensive
and slow going. Doubling the sample size of a trial will double
its cost and probably double the time to get results — something
neither sponsors nor the community want. Still, we need to get better
information about the effects of drugs on women. Body weight, hormonal
variation, and menstruation are understudied variables. The nature,
frequency and severity of toxicities seem to be different for women.
Women may typically have lower viral loads than men. Add to these
genetic factors and differences in immunological response —
which we understand even less — and our ignorance seems appalling.
But there are some immediate steps that sponsors can take to start
producing improved woman-specific data in two critical areas: pharmacokinetics
and safety. Pharmacokinetics (PK) is the study of how a drug is
absorbed and distributed as it moves through a body. If women process
and eliminate drugs at different rates than men — and there
is evidence that they may — then women risk inadequate viral
suppression (if drug levels are too low) or increased toxicity (if
drug levels are too high). Safety studies rely on time and numbers
of patients to uncover a drug's side effects. The number of women
receiving a new drug and the length of time they are studied need
to be increased if we hope to understand a drug's safety profile
before it goes to market. Specifically:
- Continue intensive, longer-term PK studies in women after the
initial Phase I studies are complete. We need to know about possible
dose adjustments before large efficacy trials begin.
- Start expanded access programs early and promote enrollment
from sites that treat women in significant numbers. If slots are
limited, preferentially enroll women — expanded access programs
are safety studies, too.
- Increase basic science research on all factors affecting drug
metabolism in women. Centers of PK studies such as the University
of Liverpool, UK should be doing much more.
Efficacy data from HIV drug trials in the U.S. are unlikely to
ever provide statistically significant results when stratified for
female gender. Industry should take proactive steps to develop supplementary
data on two key areas where woman-specific information is lacking:
pharmacokinetics and safety. Patients and doctors will have more
confidence extrapolating efficacy data to women if there are studies
to reassure them that a drug is biologically available and that
it is safe.
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